1,2,3,6-tetrahydropyrimidine-2-one compositions and therapeutic methods therewith for sexual disfunction

ABSTRACT

A therapeutic composition is provided that comprises a 1-R1-phenyl, 4-R2-phenyl substituted 1,2,3,6-tetrahydropyrimidine-2-one sensory nerve receptor agonist in a therapeutically effective amount. The sensory nerve receptor agonist may be represented by the general formula 1-[R1-phenyl]-4-[R2-phenyl]-1,2,3,6-tetrahydropyrimidine-2-one wherein: R1 is -hydroxy, -chloro, - fluoro, -alkyl, -acetoxy, -trifluoromethyl ; and R2 is -nitro, -chloro, -fluoro, -alkyl, -trifluoromethyl. Therapeutic compositions of the invention elicit soothing, cooling, and stimulatory effects when formulated for topical delivery to human sexual organs and to anorectal areas of the body and are useful to alleviate dysfunction in sexual response and intercourse for both men and women.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation-in-part of Ser. No. 10/139193,filed May 2, 2002, inventor Wei, entitled “Therapeutic1,2,3,6-Tetrahydropyrimidine-2-One Compositions and Methods Therewith”,incorporated by reference.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] Not applicable.

BACKGROUND OF THE INVENTION

[0003] 1. Field of the Invention

[0004] This invention generally relates to a class of chemicals thatactivate receptors on sensory nerve endings of human sexual organs andtherapeutic use of these chemicals for sexual dysfunction. Thisinvention more particularly relates to therapeutic compositionspreferably formulated for topical delivery to the human sexual organsand the anorectal region. The particularly preferred embodimentcompositions are formulated as an ointment or cream and comprise“icilin”, a 1,2,3,6-tetrahydropyrimidine-2-one compound.

[0005] 2. Description of Related Art

[0006] Living organisms reproduce as this process is necessary for thepreservation of the species. In humans the delivery of sperm to egg isachieved by sexual intercourse. During coitus, male and female embraceand the male inserts the male genital organ, the penis, into the femalegenital orifice, the vagina, discharging the semen therein. Coitus iscomplex, requiring both psychogenic stimuli such as arousal, excitementand passion, and synchronized physiological processes such as bloodflow, lubrication, and muscle relaxation. Disruption of this sexualactivity by age, organic disease, or other factors may lower the qualityof life.

[0007] Sexual dysfunction has been defined as impairment during anystage of the sexual response cycle (desire, arousal, orgasm, andresolution) that prevents the individual or couple from experiencingsatisfaction as a result of sexual activity. For women, the definitionhas included those who are indifferent to sexual intercourse, who haveno response to sexual advances or stimulation, or who are unable to havean orgasm during sexual intercourse. For men, treatment has focused on“erectile dysfunction”, term used to define the condition of aconsistent inability to obtain or maintain an erection for satisfactorysexual relations. This term is more precise than “impotence”, a wordthat could be vague and pejorative. Estimates suggest that the number ofU.S. men with erectile dysfunction may be about 10 to 20 million. Theprevalence of erectile dysfunction of any degree may be as high as 39%in 40-year old men, and 67% in those aged 70 years. Ageing women alsosuffer from erectile disorders in part because after menopause drynessof the vagina and diminished arousal thresholds may cause discomfortduring intercourse.

[0008] Physiology of Sensory Nerve Endings and Sexual Function. Thepenis is composed of the head and the shaft. The glans is the smoothconelike head of the penis, and is a sexually sensitive and excitablepart of a man's body. The corona and sulcus, the ridge at the back ofthe glans at the juncture of the glans and penile shaft, is also filledwith many sensory nerve endings. When stimulated, the corona is animportant source of sexual pleasure and excitement. Another sensitivearea is the frenulum, this is the thin tissue on the underside of theglans that is also attached to the skin at the top of the penile shaft.The clitoris is the anatomical equivalent of the penis in females andshares similar morphology and physiology.

[0009] The head and surface of the penis and clitoris are denselyinnervated by free nerve endings linked to sensory neurons of the dorsaldivision of the pudendal nerve located in the sacral region of thespinal cord. Typical free nerve endings are derived from thin myelinatedaxons measuring 1 to 3 μm in diameter or from unmyelinated C fibers.These nerve endings when activated convey sensations that initiate,enhance, and perpetuate the sexual response. Other anatomical structurespresent in the head of the penis are Merkel cells, Meissner, Pacinian,and Ruffini corpuscles, and genital end bulbs, but the exact functionsof these structures are not known. I believe that receptors located onthe free nerve endings or within the corpuscles, some of which haveaxons, are likely to be the targets of drugs disclosed in the presentinvention.

[0010] Vasocongestion and erectile tumescence in both male and femalesexual organs are triggered by the sensory afferent input from thepudendal nerve, by psychic stimuli, and by associated autonomic nervoussystem reflexes. The positive sensation from stimulation of the head ofthe penis during sexual arousal, and consequent erection, is a fact ofmale experience and does not require further description. In females,clitoral stimulation results in increased clitoral length and diameter,increased blood flow and tumescence of associated structures such as thelabia folds. There is also increased vaginal secretion and lubrication,engorgement of the vaginal wall, and increased diameter of the vaginallumen. Thus, an agent that causes sexual arousal will also relieveconditions of a contracted vagina, such as vaginismus, vaginal dryness,and dyspareunia (difficult or painful coitus). Ultimately, appropriateintegration of the sensory inputs from the nerve endings of the penis orclitoris together with other stimuli culminates in orgasm, satisfaction,and termination of coitus.

[0011] Drug access to receptors is also influenced by the anatomy of thegenitalia. The intact penis is covered by one single continuous skinsheath or skin system. The folded part of the skin sheath is called theforeskin or prepuce. An unusual feature of the skin system is thetransition from a keratinized surface on the outer foreskin surface to amucocutaneous surface on the inner foreskin surface (just behind theglans). An analogous change in surface anatomy is found, for example, onthe upper and lowers lips. The absence of keratin on the inner foreskin,corona, frenulum and glans readily permits drug access to sensory nervetargets. The interplay of nerves and sensation during sexual activity isdescribed on the Web by the Circumcision Information Resource Page(www.cirp.org):

[0012] “The most important components of the physical erogenousstimulation of the penis during foreplay and intercourse are thesensations from the foreskin, frenulum band, and glans. These structureseach have their own feeling, and each contributes in its own way to theman's total experience of lovemaking. It must be emphasized thatemotional excitement is an extremely important component of sexualenjoyment, and intensifies the man's perception of any physicalsensations from his penis.

[0013] The foreskin has an inner and outer layer. The outer foreskinlayer contains nerve endings which respond to gentle touching during theearly stages of sexual arousal. This helps to trigger an erection. Thenerves of the inner and outer foreskin contribute to the experience ofpenile stimulation, up to and including orgasm. These receptors arestimulated by stretching, or when the foreskin rolls over the surface ofthe glans during intercourse or masturbation.

[0014] The foreskin contains sensory receptors called Meissnercorpuscles. We believe that these nerves, similar to nerve endings inthe fingertips, are there to provide pleasure, as well as fine sensoryperception. This seems to help a man to enjoy sex longer withoutejaculating prematurely, because he can more easily tell when he isapproaching the threshold of orgasm.

[0015] We believe that stimulation of the glans is most significant inthe later stages of sexual intercourse, when penetration is deepest andemotions are running at the highest. Sensations from the glanscontribute to the quality of the sensual experience. They are alsoapparently capable of triggering orgasm on their own.”

[0016] Nevertheless, the field of the pharmacology of sensory nerveendings is in its infancy, and little is known about the chemicalsensitivity of the nerve endings in the glans of the penis or clitoris.

[0017] Background on icilin. 1,2,3,6-Tetrahydropyrimidine-2-onecompounds were described in U.S. Pat. No. 3,821,221(inventors C. Podesvaand J. M. Do Nascimentoet al, Jun. 28, 1974). These compounds werethought to have depressant and/or stimulant effects on the centralnervous system. In 1972, an abstract described a compound in this seriescalled AG-3-5(1[2-hydroxyphenyl]-4-[3-nitrophenyl]-1,2,3,6-tetrahydropyrimidine-2-one).This prototype elicited a syndrome of “wet dog shake behavior” in ratsand monkeys accompanied by hyperthermia, hyperactivity and ptosis. Wei(Chemical stimulants of shaking behavior. Journal of Pharmacy andPharmacology 28: 722-724, 1976) provided the first detailed report ofthe actions of AG-3-5 in animals and noted that shaking behavior similarto those of a dog when wet could be evoked in various laboratory animalssuch as the rat, mouse, cat, dog, gerbils, guinea pigs and hamsters.

[0018] Subsequently, Wei (Pharmacological aspects of shaking behaviorproduced by AG-3-5, TRH, and morphine withdrawal. Federation Proceedings40: 1491-1496, 1981) reported that 0.1 mg of AG-3-5, dissolved inpropylene glycol, applied to the dorsum of the tongue elicited pricklingsensations of cold and ingestion of 6 mg, on one occasion out of three,produced sensations of coolness on the cheeks and on the inner surfacesof the arms and legs. It was hypothesized that AG-3-5 may producespecific activation of receptors for cold, and that stimulation of thesereceptors accounted for the shaking seen in laboratory animals. In asubsequent publication (E. T. Wei and D. A. Seid. AG-3-5: A chemicalproducing sensations of cold. Journal of Pharmacy and Pharmacology 35:110-112, 1983) the effects of AG-3-5 on shaking behavior in the rat werecompared to those of menthol and AG-3-5 was shown to be 400 times morepotent than menthol on a molar basis on this behavioral endpoint. AG-3-5was less toxic than menthol, as measured by the oral median lethal dosein rats. AG-3-5 was named icilin because of its cold-producingproperties.

[0019] Recently, two independent groups simultaneously cloned abiological macromolecule (called a receptor) from trigeminal sensoryneurons of the rat. These receptors belong to the transient receptorpotential (TRP) family of ion channels and responded to cold temperatureand to menthol. Using a sample provided by Wei, McKemy et al.(Identification of a cold receptor reveals a general role for TRPchannels in thermosensation. Nature 416: 52-58, 2002) showed that icilinwas about 200 times more potent than menthol in eliciting ion channelcurrent changes in the cloned and transfected TRP(M8) receptor. The ionpermeability changes elicited in transfected cells were more robust withicilin than those elicited by menthol, and the presence of extracellularcalcium was required for activity. Menthol currents did not requireextracellular calcium.

[0020] The chemical structure of icilin bears little similarity to thatof menthol; the former chemical being a pyrimidine-2-one attached to twophenyl rings, and the latter a cyclohexanol derivative. Activation ofthe TRP(M8) receptor on the neuronal membrane may lead to depolarizationof the sensory nerve ending and send action potentials towards thespinal cord and brain that are eventually recognized as psychic signalsof skin stimulation.

[0021] Background on drugs for sexual therapy. Therapy of sexualdysfunction in men and women has evolved in many directions during thepast 30 years—beginning with penile prostheses in the 1970s,intracavemous injection of drugs and a vacuum constriction device in the1980s, and now the use of transurethral alprostadil (Muse®), topicalalprostadil with a enhancer of percutaneous absorption (Topiglan®), andoral sildenafil (Viagra®). The sales of Viagra® in 2001 are estimated tobe U.S. $1.5 billion, but Viagra® has little effect on sexual arousal inwomen. Drugs that affect brain centers of sexual arousal, such asapomorphine and related analogs, have also been examined as prospectivetherapy but are not products in the market. Research on novel drugs isprimarily focused on substances that affect the hemodynamic pathways ofpenile erection. Thus, drugs that cause arterial dilation, sinusoidalexpansion, venous compression and relaxation of the intracorporealsmooth muscles have received the greatest attention.

[0022] As noted above, Viagra® has little effect on sexual arousal inwomen, but other compounds are being sold as female sexual enhancers. Inthe “Physicians Desk Reference For Nonprescription Drugs” reference ismade to Vitara™ as a “Female Sexual Aids/Enhancer.” (www.vitara.com)that is approved by the Food and Drug Administration. The activeingredients are N-methylnicotinate, Wild Yam Plant Extract (Discoreae),and dihyroepiandrostenedione (DHEA). Inactive ingredients are water,propylene glycol, glycerin, polyquatemium-37/propylene glycoldicaprylate, sorbic acid, methyl and propyl paraben, and fragrance.

[0023] Vitara™ is sold as a liquid in 1 oz bottles. It is claimed thatthe drug will cause profound vasodilation to the female genitalia andfacilitate orgasm. N-methylnicotinate is a known vasodilator and willcause a flush after application at most sites on the skin. The efficacyof this drug is uncertain.

[0024] Other drugs that have been promoted as “sexual enhancers” aftertopical application include L-arginine, niacin, N-methylnicotinate,menthol, cyclic GMP (guanosine monophosphate), and a topical creamcontaining aminophylline, isosorbide dinitrate, and co-dergocrinemesylate (Gomaa, A.; Shalaby, M.; Osman, M.; Eissa, M.; Eizat, A.;Mahmoud, M.; Mikhail, N., Topical treatment of erectile dysfunction:randomised double blind placebo controlled trial of cream containingaminophylline, isosorbide dinitrate, and co-dergocrine mesylate. BritishMedical Journal 312: 1512-1515; 1996).

[0025] In manuals on sexual foreplay, ice and ice-cream are occasionallyrecommended for stimulating arousal. Ice may be applied to the lowerback or to the nipple for its “shock value”, according to Dr. AlexComofort, author of the Joy of Sex, or ice-cream may be licked off thebody. But there is no mention of applying ice to the penis or clitorisand it may be expected that such an event would have aversiveproperties. Application of ice on skin may reduce erectile responses bycausing vasoconstriction. In the patient information pamphlet for theprescription drug Muse® (the transurethral application of alprostadilfor erectile dysfunction) it is recommended that users of the drug applyice packs to the thigh if erections are maintained longer than desired(priapism). The ice packs are to be placed on the inner thigh to shortenthe duration of the erection, since the cold “ . . . will restrict bloodflow to the penis. If used, ice packs are to be applied alternately toeach inner thigh for a period not exceeding 10 minutes.”

[0026] Menthol, a chemical that activates the cold receptor, and relatedmenthol analogs will also elicit strong cooling sensations when appliedto the penis or clitoris. The sensations evoked are, however, intenseand do not cause much sexual arousal or interest. Topical application ofdrugs with 1% alprostadil (Topiglan®) as the principal ingredient hasbeen described by Samour et al., U.S. Pat. No. 5,942,545 “Compositionand method for treating erectile dysfunction.” In this formulation,menthol is added for its local anesthetic properties with the intent ofcountering the irritation produced by the other chemicals present.

BRIEF SUMMARY OF THE INVENTION

[0027] In one embodiment of the present invention, a composition isprovided that comprises a 1-R1-phenyl, 4-R2-phenyl substituted1,2,3,6-tetrahydropyrimidine-2-one sensory nerve endings receptoragonist dispersed in a vehicle that is therapeutically effective whenapplied topically to human sexual organs or to anorectal areas of thebody. The sensory nerve endings receptor agonist may be represented bythe general formula1-[R1-phenyl]-4-[R2-phenyl]-1,2,3,6-tetrahydropyrimidine-2-one wherein:R1 is -hydroxy, -chloro, - fluoro, -alkyl (with about 2 to 4 carbons),-acetoxy, -trifluoromethyl; and R2 is -nitro, -chloro, -fluoro, -alkyl,-trifluoromethyl.

[0028] A particularly preferred sensory nerve endings receptor agonistembodiment is called “icilin” and a particularly preferred compositionhas icilin dispersed as an emulsion in a dermatologically acceptablevehicle, such as an ointment or cream. Icilin formulated andadministered topically as an ointment or cream offers improvedtherapeutic benefit for the treatment of sexual dysfunction. Thus, forexample, a particularly preferred method of treating sexual dysfunctionor enhancing sexual pleasure in a human comprises topically applying acomposition comprising1-[2-hydroxy]-4-[3-nitrophenyl]-1,2,3,6-tetrahydropyridimine-2-one or ananalog to the gentalia or anorectal area, wherein the1-[2-hydroxy]-4-[3-nitrophenyl]-1,2,3,6-tetrahydropyridimine-2-one or ananalog is preferably in an amount of at least about 0.1 wt. % of thecomposition, more preferably from about 0.1 wt. % to about 20 wt. % ofthe composition.

[0029] Thus, the present invention describes certain compounds thatspecifically activate sensory nerve endings located in the genitalia andanorectal area for both men and women. Activation of these nerve endingson the head of the penis or clitoris or anus can cause sexual arousal orenhance sexual response and act as aphrodisiacs. I describe herecompositions and methods for the topical application of1,2,3,6-tetrahydropyrimidine-2-one compounds that have the propertiesof: 1) eliciting pleasant sensations from the penis and clitoris 2)lowering the threshold for tumescence under the appropriate setting, 3)increasing the mind set of the subject towards sexual intercourse, and4) increasing the duration of intercourse. Use of these therapeuticcompositions is a novel strategy for the treatment of sexualdysfunction.

[0030] The advantages and aspects of the present invention will beunderstood by reading the following detailed description and theaccompanying claims.

DETAILED DESCRIPTION OF THE INVENTION

[0031] Compositions and therapeutic methods in accordance with thisinvention utilize a 1-R1-phenyl, 4-R2-phenyl substituted1,2,3,6-tetrahydropyrimidine-2-one sensory nerve endings receptoragonist,

[0032] Formula. 1: 1-R1, 4-R2, substituted1,2,3,6-tetrahydropyridimine-2-one preferably of the general formula1-[R1-phenyl]-4-[R2-phenyl]-1,2,3,6-tetrahydropyrimidine-2-one wherein:R1 preferably is -hydroxy, -chloro, -fluoro, -alkyl (with about 2 toabout 4 carbon atoms) -acetoxy, -trifluoromethyl; and R2 preferably is-nitro, -chloro, -fluoro, -alkyl (with about 2 to 4 carbons),-trifluoromethyl. I refer to the particularly preferred compound and itsanalogs as “icilin” and its analogs as “icilin analogs”. Formula 1illustrates the general formula and icilin is represented by Formula 2.

[0033] Formula 2: Icilin,1-[2-hydroxy]-4-[3-nitrophenyl]-1,2,3,6-tetrahydropyridimine-2-one.

[0034] Icilin is a lemon yellow crystalline powder with a molecularweight of 311 Daltons and a melting point of 229 to 231° C. The powderis without odor and non-irritating, meaning that it does not elicit anysmell or unpleasant sensations upon contact with the surfaces of thehuman body. The compound is stable at room temperature. Icilin isreadily soluble in organic solvents such as dimethylsulfoxide,nitromethane, dimethylacetamide and, after warming, in propanediols;slightly soluble in ethanol and acetone; and virtually insoluble inwater. Thus, icilin would be considered as a lipophilic, hydrophobiccompound that is not easily miscible with aqueous systems. Analogs oficilin, for example, with acetyoxy, ethyl, fluoro, or trifluoromethylsubstitutions, retain similar chemical and physical properties and areincluded within the scope of this invention.

[0035] In the context of this application sexual dysfunction is meant toinclude conditions of impotence in men, of frigidity in women, oferectile dysfunction in both sexes, and of unfulfilled psychic desire ofindividuals for a better experience and performance in sexualintercourse (e.g. sexual enhancement).

[0036] Sites of Action of Icilin Compounds. In the Examples, I show thaticilin and other 1,2,3,6-tetrahydropyrimidine-2-one derivatives have theproperty of stimulating sexual arousal when applied to the head of thepenis, the clitoris, or to the anorectal region. The sensations detectedfirst are a tingling or prickly sensations of the tissues, followed bypunctate discharge of cold spots, and, if the applied amount is large,e.g. 1 cc of a 2% icilin ointment, a slight feeling of wetness on thetissue surfaces. These effects are pleasant, reinforcing and,afterwards, accompanied by a desire to repeat the experience. Thesensory effects of icilin and 1,2,3,6-tetrahydropyrimidine-2-onederivatives are qualitatively different from ice and menthol.

[0037] It has been noted that application of icilin to the mucousmembranes, as described in the parent application, produces sensationsof cold, but it also produces tingling and prickling sensations. Thishas suggested to me that other modalities may be activated. The specifictypes of sensory nerve endings from where sexual arousal is initiatedafter icilin ointment application to the glans of the penis or clitorisare not known. Both sensations of tingling and of cold are felt.

[0038] As noted earlier, little is known about the chemical sensitivityof the nerve endings in the glans of the penis or clitioris. In theparent application I used the phrase “cold receptor agonist” to describethe class of compounds contemplated for use in practicing the invention.In this application, I believe that it is more precise to characterizeicilin as a “sensory nerve endings receptor agonist” rather than as a“cold receptor agonist” when describing its action on sexual organsafter topical application. However, all sensory phenomenon are detectedon nerve endings, so the cold receptor may be viewed as one subsetlocated on a sensory nerve endpoint.

[0039] The pudendal nerve, originating from the second to fourth sacralsegments, is composed of three main divisions, the dorsal nerve of thepenis (or clitoris), the perineal nerve, and the inferior rectal nerve.The skin of the human glans of the penis (or clitoris) is innervated bythe dorsal nerve. This nerve is considered essential for spontaneouserectile and ejaculatory function because section of this nerveterminates these activities. Yang and Bradley (Neuroanatomy of penileportion of the human dorsal nerve of the penis. Brit. J. Urol. 82:109-113; 1999) have shown that as dorsal nerve enters the glans itbecomes extensively branched and there is dense innervation of theglans. These authors postulate that the glans to be a sensory organ withtransmission of afferent signals through the dorsal nerve to the spinalcord and brain. During arousal, the glans distends during erection andthere is a resultant increase in the glanular surface area. Stretchingof the glans exposes more sensory nerve endings receptors tostimulation. The afferent signals sent to the central nervous systemfurther propagate the sexual response by maintaining erection orinitiating ejaculation. A similar dense innervation is seen in the humanclitoris (Baskin, L. S.; Erol, A.; Li, Y. W.; Liu, W. H.; Kurzrock, E.;Cunha, G. R., Anatomical studies of the human clitoris. J. Urol. 162:1015-1020; 1999).

[0040] The terminations of the dorsal nerve of the penis have beenexamined at higher magnification by Halata and Munger (Theneuroanatomical basis for the protopathic sensibility of the human glanspenis. Brain Research 371: 205-230, 1986). As expected, they found adense network of free nerve endings innervating the base of the dermalpapillae (the finger-like projections of the dermis) near the surface ofthe glans (see FIG. 3 in the paper by Halata and Munger). In addition,the glans contains lamellated, onion-skin like, encapsulated sensorycorpuscles called genital end bulbs, as well as smaller less complexPacinian corpuscles, Meissner corpuscles, and Ruffini corpuscles. Halataand Munger (1986) consider the inner core of genital end bulbs to be atangled skein of free nerve endings. Similar genital end bulb structuresare found in the lip, but not in other types of skin. Without beinglimited to theory, receptors located on the free nerve endings of thehead and surface of penis and clitoris are believed to be the targets ofdrugs described in this invention.

[0041] Formulation of Icilin Compounds for Topical Delivery to Targets

[0042] Methods suitable for the preparation of the Formula 1 and Formula2 compounds are described by Podesva and Do Nascimento, U.S. Pat. No.3,821,221, issued Jun. 28, 1974, incorporated herein by reference, andare exemplified by Example A hereinafter.

[0043] Pharmaceutical carriers or vehicles suitable for the topicaladministration of icilin and combinations provided herein to the penis,clitoris and/or anorectal surfaces include any such carriers known tothose skilled in the art to be suitable for the particular mode ofadministration, which in the preferred mode is topical application.These suitable carriers for composition embodiments of the invention aretypically ointments or creams preferably with an oleaginous base (e.g.to include one or more of a wax, petrolatum, mineral oil, lanolin andglycerin). Standard ointment formulations may be used for delivery tothe penis, clitoris and anorectal surfaces. Thus, particularly preferredembodiments of this invention are wherein icilin is used in anon-irritating ointment or cream.

[0044] The effective concentration of the icilin and/or icilin analog inthe carrier or vehicle may be determined empirically by testing thecompounds using in vitro and in vivo systems. Methods for preparingsolutions, emulsions and suspensions, using standard methods forformulated Medical Topicals are well known to the art (J. G. Nair,Chapt. 39: Solutions, Emulsions, Suspensions and Extracts, pg. 721-752and L. H Block, Chapt. 44, Medicated Topicals, pg. 836-857, in“Remington, the science and practice of pharmacy,” Alfonso R. Gennaro,Chairman of the editorial board and editor. 20th ed. Baltimore, Md.Lippincott Williams & Wilkins, 2000). The recipes for ointmentpreparation, for example, are also published on the Internet, such as atthe site of the School of Pharmacy, University of North Carolina(www.pharmlabs.unc.edu or www.unc.edu/courses/phar051/ointments). Theselected icilin compound of this invention may be dispersed in thevarious dermatologically acceptable vehicles as an emulsion wherein itis either in a suspension or is solubilized, and is in either theaqueous or the oil phase. The preferred dose per application would be inthe range of 0.1 mg to 50 mg per application, depending on the potencyof the icilin analog and the area of tissue to be medicated. A morepreferred dose is in the range of 1 to 15 mg per application. Theindividual doses may be repeated as necessary to achieve the desirablesensory effects.

[0045] The rate of drug absorption across the skin surface is dependenton drug concentration in the formulation, its solubility and itsoil/water partition co-efficient. The physical form of icilin to bedelivered to the receptors of the sensory nerve endings is optimized bydesign for penetration of barriers, receptor activation, and sufficientduration of action. Although icilin may be administered dissolved in asolvent such as propanediol, it is more preferably suspended in thissolvent as a solid and admixed as an emulsion in an ointment or cream,preferably with an oleaginous base. Before formulation, icilin may bemilled to a fine particle size, modified by re-crystallization to aparticle with maximal surface area, incorporated onto nanospheres, orincorporated into nanoparticles or liposomes, to maximize biologicalactivity and duration of action using such methods as are now known inthe art.

[0046] It is well understood in the art that the precise dosage andduration of treatment is a function of the tissue being treated and maybe determined empirically using known testing protocols or byextrapolation from in vivo or in vitro test data. It is to be noted thatconcentrations and dosage values may also vary with the age of theindividual treated. It is to be further understood that for anyparticular subject, specific dosage regimens should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of theformulations, and that the concentration ranges set forth herein areexemplary only and are not intended to limit the scope or practice ofthe claimed formulations.

[0047] In Example A, I describe a 2% solution of icilin formulated in anAquaphor® ointment and used for investigation. The ingredients in thecommercially available Aquaphor® ointment are petrolatum, mineral oil,ceresin, lanolin alcohol, pathenol, glycerin and bisabolol. This productis quite similar in consistency to pure petrolatum (Vaseline®), butsomewhat less viscous, and is non-irritating. The details forpreparation of the ointment are given in Example A.

[0048] The U.S. Pharmacopoeia recgonizes four general classes ofointment bases, while the North Carolina Web site(www.unc.edu/courses/phar051/ointments) describes five. The Aquaphor®formulation is in the category of “Absorption Bases (Anhydrous)”. Somefurther examples are below described.

[0049] Thus, another ointment embodiment of the invention in the“Absorption Bases (water in oil type)” would be composed of icilin,preferably from about 1.0 to 5% by weight, and containing emulsifyingwax, white petrolatum, purified water and propylene glycol, butylatedhydroxyanisole, propyl gallate, citric acid and lactic acid.

[0050] A further example of an ointment embodiment is a lotioncontaining icilin, from about 0.3 to 2% by weight, composed of a smooth,homogeneous, opaque emulsion formed from benzyl alcohol 2% (wt/wt) aspreservative, emulsifying wax, glycerin, isopropyl palmitate, lacticacid, purified water, and polyethylene glycol 400.

[0051] A yet further example of an inventive embodiment is a moreviscous ointment containing these ingredients: a homogeneous melt of50.0% methyl salicylate, 25.0% white beeswax, 25.0% anhydrous lanolin towhich is added 2% by weight of icilin. The mixture is warmed and thenallowed to solidify.

[0052] Yet another example is where icilin is formulated in HydrophilicPetrolatum USP, using 30 g cholesterol, 30 g stearyl alcohol, 80 g whitewax, 860 g white petrolatum, combined with 20 g icilin in 110 mlpropylene glycol. The finely powdered icilin is levigated thoroughlywith a small quantity of the base to form a concentrate. The concentratethen is diluted geometrically with the remainder of the base.

[0053] The just described examples of the invention are prepared bystandard procedures for preparing ointments with petrolatum oroleaginous bases.

[0054] The solvent used for suspending or dissolving icilin may be anonaqueous pharmacologically approved solvent with non-irritatingproperties. Suitable organic materials useful as the solvent or a partof a carrier system are as follows: propylene glycol, polyethyleneglycol (M.W. 200-600), polypropylene glycol (M.W. 425-2025), glycerine,sorbitol esters, butanediol and mixtures thereof. Other examples includeethoxydiglycol, and 1 methyl-2 pyrrolidone, purified water, salinesolution, polyethylene glycol, glycerine, glycerine polymethacrylate,propylene glycol, white ointment, petroleum jelly (petrolatum), lanolin,beeswax, and cholesterol; these chemicals being alone or in combination.The preferred vehicle for levigation use in the present invention is apropanediol, preferably containing in the finished product about 0.2 to5% of Formula 1 compounds by weight.

[0055] In certain situations, aqueous suspensions, gels, pastes, foams,aerosols, and sprays may also be considered for topical administration.Compositions of the present invention with icilin and/or icilin analogsmay also be formulated as liniments (defined as a preparation that maybe liquid or semiliquid intended for external application). Enhancers ofpercutaneous absorption such as cyclodextrins, dioxane and2-ethoxy-ethoxy ethanol, may also be added to achieve optimalpharmacological effect.

[0056] As noted in the Background section, there are other drugs thathave been promoted as “sexual enhancers”, such as transurethralalprostadil (Muse®), topical alprostadil with an enhancer ofpercutaneous absorption (Topiglan®), L-arginine, niacin,N-methylnicotinate, menthol, cyclic GMP (guanosine monophosphate), and atopical cream containing aminophylline, isosorbide dinitrate, andco-dergocrine mesylate These substances act by physiological mechanismsthat are different from icilin compounds, but it is within the scopecontemplated for practicing this invention to use such compounds incombination with icilin compounds to potentiate the overall drug effecton sexual dysfunction (including sexual enhancement).

[0057] In the below experimental section, Example A describes apreparation and formulation of icilin and analogs, while Examples 1-4describe therapeutic uses of the invention with human subjects.

EXPERIMENTAL EXAMPLE A

[0058] Chemical Synthesis of Icilin and Analogs. The methods of chemicalsynthesis are as described by Podesva and Do Nascimento in U.S. Pat. No.3,821,221, incorporated by reference. Briefly, a substitutedacetophenone, e.g. 3-nitroacetophenone or 3-trifluoromethylacetophenone,readily obtainable from commercial sources such as Sigma-Aldrich, Co.,was mixed with diethylamine or dimethylamine in formaldehyde andrefluxed in acidic solutions. After addition of a second substituent(e.g. ortho-aminophenol), the Mannich reaction produced a β-amino-ketonecompound (e.g. [β-ortho-hydroxyanilino]-meta-nitropropiophenone) whichwas isolated. This reagent was then reacted with potassium cyanate orsodium cyanate to produce an unstable urea intermediate that proceeds tocyclize into the tetrahydropyridimine-2-one ring, with the appropriategroups on position 1 (2-hydroxyphenyl) and 4 (3-nitrophenyl) on the1,2,3,6-tetrahydropyrimidine-2-one ring. The precipitated product wasreadily collected by filtration (which may be recrystallized usingsolvents such as ethyl acetate or purified on silica gel columns). Thefinal products are solids stable at room temperature.

[0059] Preparation of Icilin embodiment compositions: A 2% icilinointment was prepared by adding 10 grams of icilin (in powder form) to100 ml of propylene glycol (1,2-propanediol) at room temperature. Thepropylene glycol was used as “wetting (levigating) agent” to suspend theicilin in a uniform liquid medium. This liquid icilin suspension wasthen progressively admixed in batches with 400 grams of commercialAquaphor® ointment (produced by Beiersdorf, Inc. a German Company withU.S. offices in Wilton, Conn.) to obtain the test ointment, which wasstored in standard 1 oz. vials. This ointment was prepared by the DrugProduct Services Laboratory of the University of California, SanFrancisco, under the direction of an experienced Ph.D., Pharm. D.investigator.

EXAMPLE 1

[0060] A middle-aged male subject, with a significant decline in sexualenergy due to ageing, used a cotton-tipped swab stick to apply about0.15 to 0.25 cc of the 2% icilin ointment described by Example A to thehead of his penis. These trials were conducted on five separateoccasions over a period of three days. The dose in each application wasabout 3 to 5 mg of icilin. This dose was considered relatively risk-freebecause the median lethal dose of icilin in the albino rat was greaterthan 1500 mg/kg of body weight when administered intraperitoneally (Weiand Seid, 1983, supra). Within two minutes after application of theointment to the penis, tingling and prickling sensations were felt inthe corona and glans, followed by tumescence. Cooling sensations werealso felt on the penis, particularly on the inner foreskin. There was aslight sensation of “wetness” on the organ. The overall sensations werepleasant and sexually arousing and an increased state of libido wasmaintained for about two to three hours after each application and thesubject was keen to proceed to the next experiment. Application ofAquaphor® ointment without icilin did not elicit similar sensations. Theindividual subsequently felt invigorated by these experiences, he becamemore robust in his sexual activities, and his self-image improved.

EXAMPLE 2

[0061] A young adult male subject with periodic erectile dysfunction dueto work-related stress used a cotton-tipped swab stick to apply 0.2 to0.5 cc of the 2% icilin ointment to the head of his penis and thenproceeded immediately to have sexual intercourse with his partner. Itwas reported that the penis felt more rigid and that the individual hadbetter control of his sexual rhythm. The duration of intercourse wasalso extended to twice the expected normal time, the subject felt moresatisfied with the experience, and looked forward to the next encounterwith his partner.

EXAMPLE 3

[0062] Two male subjects, on separate occasions, used a cotton-tippedswab stick to apply 0.5 to 0.8 cc of the 2% icilin ointment to theanorectal area. Within several minutes, strong cooling sensations werefelt in the region around the anal sphincter extending to the scrotum.There were also punctate discharges of cold spots, so the effects werefelt as “sparkling” and “provocative.” Both male subjects concluded thatsome individuals could construe the effects of icilin at this site as anerogenous experience.

EXAMPLE 4

[0063] A female subject used a cotton-tipped swab stick to apply 0.2 to0.4 cc of the 2% icilin ointment to the upper portion on her labia andon the clitoral surface. Within two to three minutes, tingling andprickling sensations were felt in the clitoris accompanied bytumescence. The subject then proceeded to masturbate and reported thatafter icilin application orgasm could be achieved more quickly and withless effort.

[0064] These experiments illustrate that topical application of icilinto human sexual organs and the anus is non-irritating and elicitssensations that appear to arouse sexual activity. Under the appropriateenvironmental setting and the proper mind set I conclude that topicalapplication of 1,2,3,6-tetrahydropyrimidine-2-one derivatives (i.e.,icilin and its analogs) in a suitable dermatological vehicle to theseerogenous zones will enhance libido and increase the positivereinforcement from sexual intercourse; hence these pharmaceuticalformulations are potentially useful in the treatment of sexualdysfunction.

[0065] In summary, I believe that no investigations of icilin on humananogenital area have been reported in the scientific literature otherthan what is discussed or described here. I point out the uniqueproperties of icilin and describe novel compositions and preferredembodiments for therapeutic methods of use.

[0066] It is to be understood that while the invention has beendescribed above in conjunction with preferred specific embodiments, thedescription and examples are intended to illustrate and not limit thescope of the invention, which is defined by the scope of the appendedclaims.

It is claimed:
 1. A composition for the treatment of sexual dysfunction,comprising: a therapeutically effective amount of a sensory nerveendings receptor agonist having the formula1-[R1-phenyl]-4-[R2-phenyl]-1,2,3,6-tetrahydropyrimidine-2-one, whereinR1 is hydroxy, chloro, fluoro, an alkyl of about 2 to about 4 carbonatoms, acetoxy, or trifluoromethyl and R2 is nitro, chloro, fluoro, analkyl or about 2 to 4 carbon atoms or trifluoromethyl; and adermatologically acceptable vehicle in which the a sensory nerve endingsreceptor agonist is dispersed.
 2. The composition for the treatment ofsexual dysfunction as in claim 1 wherein the sensory nerve endingsreceptor agonist is in an amount of from about 0.1% w/w to about 15% w/wand is dispersed as a suspension or an emulsion.
 3. An ointment or creamcomposition comprising:1-[2-hydroxy]-4-[3-nitrophenyl]-1,2,3,6-tetrahydropyridimine-2-one or ananalog thereof in an amount of about 0.1 wt. % to about 20 wt. % of thecomposition; and, an oleaginous base.
 4. A method of treating sexualdysfunction in a human patient comprising: topically administering atherapeutically effective amount of a sensory nerve endings receptoragonist having the formula1-[R1-phenyl]-4-[R2-phenyl]-1,2,3,6-tetrahydropyrimidine-2-one, whereinR1 is hydroxy, chloro, fluoro, an alkyl of about 2 to about 4 carbonatoms, acetoxy, or trifluoromethyl and R2 is nitro, chloro, fluoro, analkyl of about 2 to 4 carbon atoms or trifluoromethyl, to a sex organ oran anorectal area of the patient.
 5. The method as in claim 4 whereinthe sensory nerve endings receptor agonist is administered as anointment or cream
 6. The method as in claim 4 wherein the sensory nerveendings receptor agonist is administered as a lotion, gel, liniment,powder, spray, foam, or in suspension or in emulsified form.
 7. Themethod as in claim 4 wherein the amount of the sensory nerve receptoragonist administered is in an amount of from about 1 mg to about 15 mgper application.
 8. A method of treating sexual dysfunction or enhancingsexual pleasure in a man, comprising: topically applying a compositioncomprising1-[2-hydroxy]-4-[3-nitrophenyl]-1,2,3,6-tetrahydropyridimine-2-one or ananalog to the penis or anorectal area.
 9. A method of treating sexualdysfunction or enhancing sexual pleasure in a woman, comprising:topically applying a composition comprising1-[2-hydroxy]-4-[3-nitrophenyl]-1,2,3,6-tetrahydropyridimine-2-one or ananalog to the gentalia.
 10. A method of treating sexual dysfunction orenhancing sexual pleasure in a human, comprising: topically applying acomposition comprising1-[2-hydroxy]-4-[3-nitrophenyl]-1,2,3,6-tetrahydropyridimine-2-one or ananalog to the gentalia or anorectal area, the1-[2-hydroxy]-4-[3-nitrophenyl]-1,2,3,6-tetrahydropyridimine-2-one or ananalog being in an amount of at least about 0.1 wt % of the composition.